The Phosphoinositide Kinase PIKfyve Promotes Cathepsin-S-Mediated Major Histocompatibility Complex Class II Antigen Presentation
Maksim V. Baranov,
Frans Bianchi,
Anastasiya Schirmacher,
Melissa A.C. van Aart,
Sjors Maassen,
Elke M. Muntjewerff,
Ilse Dingjan,
Martin ter Beest,
Martijn Verdoes,
Samantha G.L. Keyser,
Carolyn R. Bertozzi,
Ulf Diederichsen,
Geert van den Bogaart
Affiliations
Maksim V. Baranov
Department of Tumor Immunology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 28, 6525GA Nijmegen, the Netherlands
Frans Bianchi
Department of Tumor Immunology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 28, 6525GA Nijmegen, the Netherlands; Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7, Groningen 9747 AG, the Netherlands
Anastasiya Schirmacher
Institute of Organic and Biomolecular Chemistry, Georg-August-University of Göttingen, Tammannstr. 2, 37077 Göttingen, Germany
Melissa A.C. van Aart
Department of Tumor Immunology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 28, 6525GA Nijmegen, the Netherlands
Sjors Maassen
Department of Tumor Immunology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 28, 6525GA Nijmegen, the Netherlands; Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7, Groningen 9747 AG, the Netherlands
Elke M. Muntjewerff
Department of Tumor Immunology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 28, 6525GA Nijmegen, the Netherlands
Ilse Dingjan
Department of Tumor Immunology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 28, 6525GA Nijmegen, the Netherlands
Martin ter Beest
Department of Tumor Immunology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 28, 6525GA Nijmegen, the Netherlands
Martijn Verdoes
Department of Tumor Immunology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 28, 6525GA Nijmegen, the Netherlands
Samantha G.L. Keyser
Department of Chemistry, University of California, Berkeley, CA 94720, USA
Carolyn R. Bertozzi
Department of Chemistry and Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA
Ulf Diederichsen
Institute of Organic and Biomolecular Chemistry, Georg-August-University of Göttingen, Tammannstr. 2, 37077 Göttingen, Germany
Geert van den Bogaart
Department of Tumor Immunology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 28, 6525GA Nijmegen, the Netherlands; Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7, Groningen 9747 AG, the Netherlands; Corresponding author
Summary: Antigen presentation to T cells in major histocompatibility complex class II (MHC class II) requires the conversion of early endo/phagosomes into lysosomes by a process called maturation. Maturation is driven by the phosphoinositide kinase PIKfyve. Blocking PIKfyve activity by small molecule inhibitors caused a delay in the conversion of phagosomes into lysosomes and in phagosomal acidification, whereas production of reactive oxygen species (ROS) increased. Elevated ROS resulted in reduced activity of cathepsin S and B, but not X, causing a proteolytic defect of MHC class II chaperone invariant chain Ii processing. We developed a novel universal MHC class II presentation assay based on a bio-orthogonal “clickable” antigen and showed that MHC class II presentation was disrupted by the inhibition of PIKfyve, which in turn resulted in reduced activation of CD4+ T cells. Our results demonstrate a key role of PIKfyve in the processing and presentation of antigens, which should be taken into consideration when targeting PIKfyve in autoimmune disease and cancer. : Molecular Mechanism of Gene Regulation; Immunology; Immune Response Subject Areas: Molecular Mechanism of Gene Regulation, Immunology, Immune Response
